tbuckley/cabot-search huggingface dataset:
Matching-adjusted indirect comparison (MAIC) of mobocertinib versus amivantamab in patients with non–small cell lung cancer (NSCLC) with <i>EGFR</i> exon 20 insertions (ex20ins).
Authors: Sai-Hong Ignatius Ou, Thibaud Prawitz, Huamao Mark Lin, Jin-Liern Hong, Minal Tan, Irina Proskorovsky, Luis Hernandez, Shu Jin, Pingkuan Zhang, Jianchang Lin, Jyoti D. Patel, Danny Nguyen, Joel W. Neal
Journal: Journal of Clinical Oncology (2022)

9115 Background: Mobocertinib (mobo) and amivantamab (ami) are FDA-approved treatments for patients (pts) with locally advanced or metastatic NSCLC with EGFR ex20ins whose disease progressed on or after platinum-based chemotherapy. An unanchored MAIC was used to compare confirmed overall response rate (cORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS) between mobo and ami. Methods: Clinical outcomes were compared in platinum-pretreated pts with EGFR ex20ins+ NSCLC treated with mobo 160 mg QD in a phase I/II single-arm study (NCT02716116, cut-off 1 Nov 2020, n=114) or with ami 1,050 mg (1,400 mg, ≥80 kg) in a phase I single-arm study (NCT02609776, cut-off 8 June 2020, n=81). Differences in baseline characteristics reported in both studies, including age, race, sex, smoking status, Eastern Cooperative Oncology Group, histology, sites of metastasis (brain, bone and liver), time from advanced diagnosis, number of prior lines of therapy, prior immuno-oncology therapy, prior EGFR tyrosine kinase inhibitor treatment and prior EGFR ex20ins targeted therapy, were adjusted with MAIC. Results: After MAIC weighting all reported baseline characteristics were balanced between mobo and ami. OS and cORR per investigator assessment (INV) were similar between mobo and ami (Table). cORR per independent review committee (IRC) was numerically higher for ami (odds ratio [OR]=0.64, p value=0.230). For PFS per IRC, the adjusted hazard ratio (HR) was numerically favorable for mobo (HR=0.82, p value=0.417). Among the responders, DoR was longer for mobo (DoR per INV: HR=0.44, p value=0.049; DoR per IRC: HR=0.56, p value=0.149). Conclusions: Mobo and ami appear to have overall similar efficacy. As each has a different mechanism of action and route of administration, they provide multiple options in the treatment of EGFR ex20ins+ NSCLC. Clinical trial information: NCT02716116. [Table: see text]
MEDB-64. Are Rab GTPases metastatic drivers in metastatic medulloblastoma?
Authors: Susannah Entwistle, Hannah K Jackson, Ian Kerr, Beth Coyle, Alistair Hume
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is the most common malignant paediatric brain cancer with poorer prognosis related to the onset of metastasis. It has four molecular subgroups; Wingless (WNT), Sonic Hedgehog (SHH), group 3 and group 4, of which group 3 is the most likely to be metastatic and is therefore associated with the poorest prognosis. Exosomes are small membrane-bound extracellular vesicles of endosomal origin which contain a variety of cargo including RNA and proteins. Increased exosome release is connected with disease progression and metastasis in multiple cancers. Rabs are a family of small GTPases (70 in humans) which regulate vesicle trafficking. Several Rabs are known to regulate exosome biogenesis and secretion and may thereby contribute to cancer progression. The role of Rabs in metastatic medulloblastoma is unclear. We aim to explore whether Rabs contribute to the progression of metastatic medulloblastoma through the exosome biogenesis and secretion pathways. Through analysis of literature, databases such as ExoCarta.org, the R2: Genomics analysis and visualisation platform, and mRNA content of medulloblastoma exosomes, five novel Rab candidates were identified that may contribute to disease progression in group 3 medulloblastoma. Gene expression of these Rabs was then verified across SHH, group 3 and group 4 patient-derived cell lines using RT-qPCR, with candidate Rab expression confirmed in the three subgroups. Presence of Rab mRNA has also been found in exosomes derived from group 3 and group 4 patients, with an enrichment in group 3 exosomes. Current and future work aims to determine the potential roles of Rabs in medulloblastoma pathogenesis, and to determine whether Rabs contribute to increased exosome biogenesis which drives metastasis or are metastatic drivers in medulloblastoma themselves. Therefore, experiments to characterise Rab candidate protein expression within cells and assess their function after knockdown are necessary and timely.
Delays in care following a COVID diagnosis.
Authors: Samyukta Mullangi, Emeline Mariam Aviki, Yuan Chen, Mark E. Robson, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2022)

e18675 Background: We sought to describe factors associated with treatment delay among cancer patients with COVID-19. Methods: We conducted a retrospective analysis of de-identified data from the ASCO COVID-19 Cancer Data Registry, a longitudinal cohort study launched in April 2020 with 60 community and academic practices. We evaluated all patients who were documented as having therapy (anticancer drug therapy, surgery or radiation therapy) scheduled at the time of entry into the registry due to a positive SARS-CoV-2 test result. Treatment delay were defined based on length of delay: on schedule or within 14 days, and delay &gt; 14 days or discontinued entirely. The latter is defined as “delay in care”. We used univariate and multivariate logistic analyses to address these questions. Results: At the time of data analysis, 3028 patients were included in the registry, of which 2103 had scheduled drug therapy, 125 had scheduled surgery, and 202 had scheduled radiation. 46% of patients had a drug delay or discontinuation of care. A multivariable logistic regression found that delays were higher among Black patients relative to white patients (OR 1.73, 95%CI 1.27, 2.35), and Hispanic or Latino patients compared to non-Hispanic or Latino patients (OR 1.95, 95%CI 1.36, 2.80). Compared with patients with 0-1 comorbidities, having 2 or more comorbidities was associated with delay in treatment (OR 1.26, 95%CI 1.01, 1.56). Having metastatic disease, rather than local or regional disease (OR 1.61, 95%CI 1.28, 2.04), and having any COVID-19 complications compared to none (OR 1.49, 95%CI 1.22, 1.83) were associated with delay. Relative to the initial outbreak of the pandemic from March-June 2020, having a COVID-19 diagnosis later in the pandemic was associated with lower likelihood of delay (OR 0.45, 95%CI 0.26, 0.74). 47% (95/202) of patients had a radiation delay or discontinuation of care. Factors associated with radiation delay included having 2 or more comorbidities (OR 2.78, 95%CI 1.22, 6.53). 71% (89/125) of patients had a surgical delay or discontinuation care. Factors associated with surgical delay included female sex (OR 6.05, 95%CI 1.34, 34.6), being in the South compared with being in the Midwest (OR 9.00, 95%CI 1.97, 49.0). Counter-intuitively, having 2 or more comorbidities was associated with a lower likelihood of delay (OR 0.27, 95%CI 0.09, 0.90). Being diagnosed with COVID-19 in July-Sept 2020 was associated with lower likelihood of delay (OR 0.07, 95%CI 0.01, 0.49). Conclusions: Previous data has shown persistent disparities in COVID-19-related outcomes in subgroups of disadvantaged and minority patients and populations. Data from our study shows that another disparity borne of treatment delays for chronic disease in the setting of a positive SARS-CoV2 test may also contribute to overall poor outcomes in these vulnerable populations.
HGG-28. CLIC1 and CLIC4 ion channel deficiency confers increased sensitivity to tumour treating fields and improved survival in paediatric glioblastoma
Authors: Michaela Griffin, Stuart Smith, Surajit Basu, Raheela Khan
Journal: Neuro-Oncology (2022)

Abstract Paediatric Glioblastoma Multiforme (pGBM) is a lethal brain cancer with an average survival of 14 months. Due to the scarcity of effective treatment, pGBM forms the leading cause of CNS cancer death in children. Optune™ is a non-invasive therapy that uses alternating electric fields – coined TT fields - to disrupt cancer cell division, however it is not currently approved in children. Evidence shows that ion channels not only regulate electrical signalling of excitable cells, but also play a crucial role in the development and progression of brain tumours, essential in cell cycle control and therefore presenting as valuable therapeutic targets. Candidate ion channel genes (ICG) associated with the malignant status of high-grade glioma (HGG) were identified via multivariate analysis of in-house and publicly available data sets. RNA sequencing of in-house patient tissues revealed an increased expression of CLIC1 and CLIC4, with pHGG exhibiting increased expression at protein and RNA levels in both the Paugh data set and in-house primary cell lines and TMAs. Clinical correlation determined that CLIC4 and CLIC1 deficiency was associated with increased overall survival (p=&amp;lt;0.03). siRNA depletion of CLIC1 and CLIC4 propagated a reduction in the proliferation, migration and invasion of pHGG cell lines and resulted in cell cycle arrest. Furthermore, CLIC1 and CLIC4 deficiency exacerbated the killing capacity of TT fields. Whole transcriptome gene expression analysis (Human Clairom™ Array) of paediatric GBM cell lines treated with tumour treating fields and found that cells treated with TTfields exhibited a down-regulation in CLIC1 and CLIC4 compared to untreated cells. These data provide rationale that genetic, electrical, and pharmacological manipulation of ion channels will reduce the capacity of childhood brain tumours to proliferate and invade. Therefore, may be a suitable target for combination therapy to enhance the treatment efficacy of TTfields and help bring this non-invasive therapy to paediatric patients.
Optimizing selective clamping during 3-D guided robotic partial nephrectomy: The application of a mathematical tool to precisely establish the perfusion areas of the organ
Authors: D. Amparore, F. Piramide, A. Pecoraro, P. Verri, E. Checcucci, S. De Cillis, A. Piana, G. Volpi, M. Sica, S. Granato, S. Piscitello, D. Zamengo, A. Quarà, M. Manfredi, C. Fiori, F. Porpiglia
Journal: European Urology (2022)
Identifying biomarkers associated with disease-free survival in stage I non–small cell lung cancer.
Authors: Christopher W. Seder, Hita Moudgalya, Andrew E. Donaldson, Kayla Viets Layng, Elizabeth Mauer, Janakiraman Subramanian, Cristina L. Fhied, Nicole Geissen, Gillian Alex, Justin Karush, Michael J. Liptay, Jeffrey Allen Borgia
Journal: Journal of Clinical Oncology (2022)

8543 Background: Patients with early stage, non-small cell lung cancer (NSCLC) with solitary pulmonary lesions ≤4 cm typically have favorable outcomes. However, disease recurrence impacts up to 30% of patients, leading to either additional surgical or systemic interventions. New methods to risk stratify patients based on clinical and molecular parameters may improve our ability to select cases that would benefit from more frequent surveillance or enrollment in clinical trials evaluating systemic therapy. Methods: We retrospectively analyzed data from 179 patients with early stage (T 1a-2a N 0 M 0 ) NSCLC from a single institution. All patients had anatomic resection, negative margins, and systematic nodal sampling. Clinical and demographic data were abstracted from patient charts and tumor samples were molecularly profiled using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage, whole exome-capture RNA-seq). Pathogenic alterations (single nucleotide variants and insertion/deletions) and RNA expression were examined. Bivariate Cox-proportional Hazards models were used to assess the association of individual clinical, demographic, and molecular variables with recurrence-free survival, defined as the time from surgery until recurrence or death. Results: Our dataset included 166 stage IA1-3 patients and 13 stage IB patients, of which 36 patients experienced a recurrence or death event after surgery. Clinical and DNA-seq data was available for all patients, and RNA expression data was available for 172 patients. Across all patients, the most common somatically mutated genes were TP53 (33% of tumors) and KRAS (16% of tumors), consistent with previous studies. Increasing log 10- RNA expression for NTRK1 (HR: 5.95; 95% CI, 1.16-30.4; p = 0.027) and CD274 (PD-L1) (HR: 7.88; 95% CI, 1.61-38.6; p = 0.013) and decreasing log 10- RNA expression for EGFR (HR: 0.24; 95% CI, 0.05-1.21; p = 0.071) and ERBB2 (Her2) (HR: 0.20; 95% CI, 0.04-0.97; p = 0.042) were associated with increased risk of recurrence or death. Conclusions: Increased expression of NTRK1 and CD274 (PD-L1) and decreased expression of EGFR and ERBB2 (Her2) were associated with a increased risk for recurrence following surgery. This may have mechanistic implications for heightened tumor aggressiveness and/or metastatic potential. Future work will expand our cohort and validate our findings in a broader set of early-stage NSCLC patients.
MEDB-51. Impact of residual tumor on outcomes in children and adolescents with medulloblastoma in the German HIT-cohort
Authors: Stella Wolgast, Denise Obrecht, Martin Mynarek, Brigitte Bison, Rudolf Schwarz, Torsten Pietsch, Rolf-Dieter Kortmann, Monika Warmuth-Metz, Stefan Rutkowski
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: To date, a historical threshold of 1.5cm2 extent of resection (EOR) of the primary tumor is used for risk stratification in pediatric medulloblastoma (MB). METHODS: Data of n=348 patients with MB included into the German HIT-MED studies and registries from 2000-2017 were retrospectively analyzed. Kaplan-Meier statistics and Cox regressions were calculated to determine the influence of EOR, histological and molecular subtype, MYC/N-amplification and presence of metastases at first diagnosis on overall and progression-free survival (OS/PFS). ROC curves were calculated aiming at identifying a new EOR cut-off. RESULTS: Median age at diagnosis was 6.8 [0.1-20.5] years. After initial surgery, residual tumor (R) ≥1.5cm2 was present in 129/348 patients (37%). 57% presented with additional metastases. In most cases, classic histology was found (71%, DMB/MBEN: 20%, LC/AMB: 9%). Molecular subtype was nonWNT/nonSHH in 68% (Group 4: 37%, Group 3: 31%), WNT in 6% and SHH-activated types in 26% of evaluated cases (n=208). MYC/MYCN-amplification was present in 5 and 4%, respectively. 41/348 patients received additional surgery, resulting in 73% GTR (not reported: n=22). EOR had no significant impact on OS/PFS (GTR: 5y-OS/PFS 69.9±3.4/57.6±3.7%, STR: 5y-OS/PFS 71.4±4.1/56.2±4.5%, p=0.6/0.8; Cox: p=0.2/0.4; median follow-up 8.4 [0.1-18.0] years). ROC curves did not identify a significantly improved limit for outcome-relevant EOR cut-off. Analyses confirmed less favorable OS/PFS for patients with metastatic disease (p=0.04/p&amp;lt;0.05), LC/AMB (p&amp;lt;0.05/p&amp;lt;0.05), Group 3 (p&amp;lt;0.05/p&amp;lt;0.05), and MYC-amplification (p&amp;lt;0.05/p&amp;lt;0.05). Cox regression confirmed an increased risk for Group 3 (OS: HR=4.74, p&amp;lt;0.05, PFS: HR=2.90, p&amp;lt;0.05) and M+ (PFS: HR=2.69, p&amp;lt;0.05). DISCUSSION: No distinct influence of EOR &amp;lt;/≥1.5cm2 on OS/PFS in pediatric MB was detected. The relevance of EOR and the historical limit of 1.5cm2 should be further investigated in distinct MB subtypes and in context of other risk factors.
Observational study evaluating wait time and clinical outcomes in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who received chimeric antigen receptor (CAR) T-cell therapy (T-CT).
Authors: Danielle Chun, Yu Yin, Alf Bernhardt, Lynn Sanders, Emily Brouwer
Journal: Journal of Clinical Oncology (2022)

e19577 Background: 5-year survival rates for DLBCL pts in the first-line setting range from 60% to 70%. Up to 50% of pts become refractory to or relapse (r/r) after treatment. Autologous CAR T-CT has shown efficacy in r/r DLBCL in ≥2 lines of treatment but faces significant challenges with cell collection and manufacturing that may delay pt treatment. This study assessed the impact of wait time for CAR T-CT (time between apheresis and CAR T-CT administration) on progression-free survival (PFS) in DLBCL pts. Methods: Data from pts in the electronic health record-derived de-identified US-based Flatiron Health database, who had a DLBCL diagnosis after Jan 1, 2011, and a documented CAR T-CT administration date, were included. Pts missing a documented apheresis date were excluded. Demographic and clinical characteristics were assessed within 6 months (mos) prior to index date (CAR T-CT administration). Pts were followed from index date to the first of pt death or end of data availability. Given no established clinically relevant cut points, short wait time was defined as &lt; median time between apheresis and index date. Long wait time was defined as ≥ median time. 3-, 6-, and 12-mo PFS probabilities (95% confidence intervals [CIs]) by wait time were reported. Results: 91 DLBCL pts received CAR T-CT; 78 had a documented apheresis date. Median time from apheresis to index date was 37 days (interquartile range: 25, 116). 55% of pts experienced longer wait times (≥37 days). 45% experienced shorter times (&lt;37 days). Pts were mostly white (80%–84%), male (57%–65%), and older (median: 60–67 years), with similar median follow-up time from index (4.0–4.7 mos). More pts with short wait times had stage 4 disease than those with long wait times (51% vs 28%). 71% of pts with shorter wait times received axicabtagene ciloleucel. Among those with long wait times, 72% received tisaggenlecleucel. More pts with long wait times received bridging therapy (66% vs 74%). Pts with short wait times had a higher 3-mo PFS probability than pts with long wait times. The 6- and 12-mo PFS probabilities were lower in those with shorter wait times (Table). No statistical comparisons were made due to small sample size. Conclusions: This real-world study showed no meaningful differences in PFS between wait times in DLBCL pts in the United States. Results from this study show evidence of channeling bias which is an important consideration for evaluating real-world data to construct external control arms. Future studies are needed to further evaluate the impact of delayed treatment in pts with r/r DLBCL. Funding: Takeda Development Center Americas, Inc.[Table: see text]
Photo‐Crosslinked Antimicrobial Hydrogel Exhibiting Wound Healing Ability and Curing Infections In Vivo
Authors: Rajib Dey, Riya Mukherjee, Jayanta Haldar
Journal: Advanced Healthcare Materials (2022)

With the increasing focus on healthcare research in the current times, therapeutic and biomaterial interventions for healing of wounds and mitigation of wound-associated infections have seen expedited progress. Conventional approaches consist of release-active gels, which demonstrate leaching of antimicrobials, such as antibiotics, metal ions, etc. However, these systems suffer from the disadvantages of burst release, reservoir exhaustion, and associated toxicity. In this report, intrinsically antimicrobial hydrogel (HyDex) is developed by one-pot UV crosslinking of methacrylated dextran, polyethylene glycol diacrylate, and cationic lipophilic methacrylate with varied hydrophobic chain, which displays broad-spectrum antimicrobial activity, hemostatic ability, and rapid wound closure efficacy. The optimized hydrogel exhibits potent antimicrobial efficacy against multidrug-resistant Gram-positive and Gram-negative bacteria as well as against pathogenic fungus Candida albicans. The HyDex hydrogel shows rapid arrest of bleeding in mice liver puncture model. The hydrogel kills carbapenem-resistant Acinetobacter baumannii in a murine model of burn wound infection with >99% reduction in bacterial burden. Furthermore, this hydrogel displays significant reduction in inflammatory responses, with accelerated wound healing in rat deep wound model. Collectively, these results imply the excellent promise held by lead hydrogel to be developed for tackling deep tissue wounds, notorious infections, and resulting inflammatory responses.
T-DXd: New Standard for HER2-Low Breast Cancer
Journal: Cancer Discovery (2022)

Findings from the phase III DESTINY-Breast04 trial indicate that the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is effective for patients with inoperable/metastatic HER2-low breast cancer. T-DXd should be considered a new standard of care for these patients, who otherwise have limited options.
Intracellular Sensing of <scp>DNA</scp> in Autoinflammation and Autoimmunity
Authors: Susan MacLauchlan, Katherine A. Fitzgerald, Ellen M. Gravallese
Journal: Arthritis & Rheumatology (2022)

Evidence has shown that DNA is a pathogen‐associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen‐specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA–sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes–associated vasculopathy with onset in infancy and Aicardi‐Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA–sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.
Mendelian imputation of parental genotypes improves estimates of direct genetic effects
Authors: Alexander I. Young, Seyed Moeen Nehzati, Stefania Benonisdottir, Aysu Okbay, Hariharan Jayashankar, Chanwook Lee, David Cesarini, Daniel J. Benjamin, Patrick Turley, Augustine Kong
Journal: Nature Genetics (2022)

Effects estimated by genome-wide association studies (GWASs) include effects of alleles in an individual on that individual (direct genetic effects), indirect genetic effects (for example, effects of alleles in parents on offspring through the environment) and bias from confounding. Within-family genetic variation is random, enabling unbiased estimation of direct genetic effects when parents are genotyped. However, parental genotypes are often missing. We introduce a method that imputes missing parental genotypes and estimates direct genetic effects. Our method, implemented in the software package snipar (single-nucleotide imputation of parents), gives more precise estimates of direct genetic effects than existing approaches. Using 39,614 individuals from the UK Biobank with at least one genotyped sibling/parent, we estimate the correlation between direct genetic effects and effects from standard GWASs for nine phenotypes, including educational attainment (r = 0.739, standard error (s.e.) = 0.086) and cognitive ability (r = 0.490, s.e. = 0.086). Our results demonstrate substantial confounding bias in standard GWASs for some phenotypes.